Does this look like mitochondrial dysfunction?

[Jesse2233]

Hey everyone -

I'm questioning whether my fatigue, lightheadedness, and poor stamina are due to POTS (not enough blood to my brain), hypometabolism (specifically a deficiency in TCA enzymes or glycolysis) , elevated TNFa (from fighting pathogens), or all of the above.

Genova NutraEval seems to indicate some dysfunction, but UCLA Urine Organic Acid testing appears normal (although metabolite levels have fluctuated). Given that UCLA is a highly rated research university I'm inclined to trust their results, but they don't test as many metabolites as Genova.

Both seem to show I'm in ketosis which makes sense given my diet.

Any help on squaring and contextualizing these results would be greatly appreciated.

ARUP August Cytokine panel

TNFa - 78 (ref <=22)

UCLA Lactic / Pyruvic Ratio:

Lactic Acid 1.68 / Pyruvic Acid = 0.146

UCLA Urine Organic Acid results over time:

UCLA Plasma Amino Acid results over time:

NutraEval from June

Tagging some knowledgeable folks:

@Hip @alicec @Freddd @caledonia @halcyon @Learner1

Thanks!

 

[rodgergrummidge]

Hey everyone -

I'm questioning whether my fatigue, lightheadedness, and poor stamina are due to POTS (not enough blood to my brain), hypometabolism (specifically a deficiency in TCA enzymes or glycolysis) , elevated TNFa (from fighting pathogens), or all of the above.

Genova NutraEval seems to indicate some dysfunction, but UCLA Urine Organic Acid testing appears normal (although metabolite levels have fluctuated). Given that UCLA is a highly rated research university I'm inclined to trust their results, but they don't test as many metabolites as Genova.

Both seem to show I'm in ketosis which makes sense given my diet.

Any help on squaring and contextualizing these results would be greatly appreciated.

UCLA Lactic / Pyruvic Ratio:

Lactic Acid 1.68 / Pyruvic Acid = 0.146

Hi @Jesse2233 , you indicate that you are in ketosis. What is your % carbohydrate/protein/fat intake in calories?

A low-carb ketogenic diet doesnt provide much glucose for glycolysis so you wouldnt expect high levels of either pyruvate or lactate. Which is the case in your blood samples.

However, with insufficient carbs, you should see an increase in fatty acid oxidation which can be measured by ketones in the blood or urine. Fatty oxidation leads to the production of Acetyl-CoA which is then converted to the 3 main ketones i) Acetone which is lost on the breath ii) Acetoacetate which can be reliably measured in the urine (keto-dipsticks to monitor urine acetoacetate can be bought fairly cheaply online or at the chemist so you can test at home and monitor your ketosis) and iii) 3-hydroxybutyrate which can be reliably measured in the blood. Your urine results demonstrated elevated levels of acetoacetate indicating that you were in ketosis in June and September.

It would have been good to perform 3-hydroxybutyrate analysis in the blood to back up the urine acetoacetate analysis (perhaps ask for it next time)

The other consequence of a ketogenic diet is that energy must be generated from alternate non-carb sources such as amino acids (from diet or produced by protein breakdown). For example, Leucine, Isoleucine, phenylalanine, tryptophan and tyrosine play an important role in mitochondrial energy production because they all enter the TCA cycle via acetyl-CoA (at the top). You have elevated levels in 3/5 of these ketogenic amino acids in the blood which would suggest that you may have a reduced ability to convert Leucine, Isoleucine, phenylalanine, tryptophan and tyrosine into acetyl-CoA and fuel the TCA cycle.

In such a scenario, the TCA would not only be faced with inadequate supply of pyruvate (from carbohydrate breakdown and glycolysis), but also an inadequate supply of Acetyl-CoA from ketogenic amino acids. Under such conditions, you may have significant difficulties in generating sufficient ATP leading to exercise intolerance and CFS symptoms.

How long have you been on a ketogenic diet? How do you feel? Do you feel better or worse on your ketogenic diet?

I am currently on a ketogenic diet (3.5 weeks and I am currently ketogenic). So far, it made my CFS symptoms worse. I not sure how long to persist....... I miss my carbs!

Rodger

EDIT: just realized that your pic of the TCA cycle (above) were actual pathology results from NutraEvil. I thought you included it just to illustrate the cycle. Note that NutraEvil has made a mistake. Not all amino acids enter via Acetyl-CoA as their illustration indicates. But 3/5 amino acids that do enter the TCA via Acetyl-CoA (listed above) are elevated and so might be really important in understanding and tackling your disease.

 

[Nickster]

Hey everyone -

I'm questioning whether my fatigue, lightheadedness, and poor stamina are due to POTS (not enough blood to my brain), hypometabolism (specifically a deficiency in TCA enzymes or glycolysis) , elevated TNFa (from fighting pathogens), or all of the above.

Genova NutraEval seems to indicate some dysfunction, but UCLA Urine Organic Acid testing appears normal (although metabolite levels have fluctuated). Given that UCLA is a highly rated research university I'm inclined to trust their results, but they don't test as many metabolites as Genova.

Both seem to show I'm in ketosis which makes sense given my diet.

Any help on squaring and contextualizing these results would be greatly appreciated.

ARUP August Cytokine panel

TNFa - 78 (ref <=22)

UCLA Lactic / Pyruvic Ratio:

Lactic Acid 1.68 / Pyruvic Acid = 0.146

UCLA Urine Organic Acid results over time:

View attachment 24560

UCLA Plasma Amino Acid results over time:

View attachment 24562

NutraEval from June

View attachment 24561

Tagging some knowledgeable folks:

@Hip @alicec @Freddd @caledonia @halcyon @Learner1

Thanks!

Jesse, I found a good mitochondria doctor in Pasadena. We had Nick scheduled to see him, but, we had to cancel since he is too sick. Private message me if you would like his information. Next year he will be doing telemedicine.

 

[Jesse2233]

Thanks @rodgergrummidge, I appreciate the analysis

Hi @Jesse2233 , you indicate that you are in ketosis. What is your % carbohydrate/protein/fat intake in calories?

Not sure on exact percentages but 99% of my diet is veggies and meat. No dairy, sugar, grains, or fruit

A low-carb ketogenic diet doesnt provide much glucose for glycolysis so you wouldnt expect high levels of either pyruvate or lactate. Which is the case in your blood samples.

Where are you seeing the high levels? My read was that pyruvate and lactate are normal

It would have been good to perform 3-hydroxybutyrate analysis in the blood to back up the urine acetoacetate analysis (perhaps ask for it next time)

That's in the NutraEval (upper left), it's quite high which in my understanding underscores that I'm in ketosis

How long have you been on a ketogenic diet? How do you feel? Do you feel better or worse on your ketogenic diet?

Eh somewhat better I guess, hard to gauge. Not worse. Been on it since getting sick 10 months ago, more strictly for the last month

 

[alicec]

Some notes, not in any particular order.

Elevated 3 OH butyric indicates ketosis.

Only leucine is consistently elevated on plasma amino acid test - ileu and phe are low in the first test, phe normal in the second, ileu elevated (though not marked by you). Could possibly indicate problem catabolising branched chain aas but not serious - or supplemental amino acids?.

First part of Kreb's cycle is reasonable, perhaps a bit on the low side but proceeding ok. Pyruvate and lactate are a bit low probably reflecting your ketogenic diet.

There's a bit of a boost to citrate, presumably reflecting sources other than CHO feeding in,

a bit of a drop off to cis aconitate possibly reflecting some oxidative stress (iron-sulfur clusters in aconitase are particularly susceptible to ROS) although isocitric is ok and this uses aconitase also - so not too serious.

A bit of a fall off back to aKG, so maybe isocitrate value is a bit inaccurate - artificially increased, or alternatively maybe there is reduced feed in of amino acids such as glutamate here. Note high glu on plasma aas - ie glu not being used?.

Elevated succinate could suggest problems with ETC and or insufficient CoQ, B2 (ie it is backing up because it's not being used properly).

Elevated malate could mean a problem with conversion to oxaloacetate (so again it is backing up) or alternatively succinate and malate are involved in other things so these could be influential.

High glu:gln on plasma aas could suggest a problem dealing with ammonia.

High beta alanine and 1 methylhistidine could just reflect high meat consumption.

 

[rodgergrummidge]

Thanks @rodgergrummidge, I appreciate the analysis

Not sure on exact percentages but 99% of my diet is veggies and meat. No dairy, sugar, grains, or fruit

Where are you seeing the high levels? My read was that pyruvate and lactate are normal

That's in the NutraEval (upper left), it's quite high which in my understanding underscores that I'm in ketosis

Eh somewhat better I guess, hard to gauge. Not worse. Been on it since getting sick 10 months ago, more strictly for the last month

Hi @Jesse2233 I was suggesting that a low-carb ketogenic diet doesnt provide much glucose for glycolysis so you 'wouldnt expect high levels of either pyruvate or lactate'.

Yes, I see your NutraEval blood 3-hydroxybutyrate now. As you say, it is high reflecting that you are in ketosis.

But i think its important to carefully work out if your 'low carb' diet is really ketogenic or whether your ketosis may be due to some other underlying metabolic issue. Its fairly easy to do. Just work out how many calories you are consuming from fats, protein and carbs on average. Your meat and vegie diet may actually contain significant carbs as many vegies are high in carbs. For example, if you are consuming ~30-40% carbs (in terms of calories) and 60-70% from protein/fats, you may not reach a ketogenic state. Thus, you may assume that your 3-hydroxybutyrate and acetoacetate readings are due to a ketogenic diet when, in fact, they may be due to metabolic defects in your carbohydrate metabolism. Work out your average % fats/proteins/carbs (calories). If your carbs are >30%, it could mean that ketogenic markers are not due to your diet, but may be due to some underlying undiagnosed metabolic defect in carbohydrate metabolism.

Perhaps relevant to some of your results, Naviaux et al also found a significant elevation if 1-methylhistidine in CFS males while McGregor et al found elevated b-alanine in CFS patients.

Lastly, it may be worthwhile to follow up your high results (at least 1 high reading in the 2 tests) for ketogenic amino acids (These are isoleucine, leucine, lysine, phenylalanine, tryptophan, and tyrosine) that enter the TCA cycle as acetyl-CoA. See below pic. The high readings may may be due to some reduced efficiency in the ability to utilize ketogenic amino acids for energy via the TCA.

good luck

Rodger

 

[Learner1]

Sorry, Jesse, not sure why the tag didn't work, but I just noticed this.

The analysis above looks good. I vote for all of the above.

The elevated TNFa is likely related to your infections. A couple of interesting discussions are here:

https://www.hindawi.com/journals/mi/2014/861231/

https://selfhacked.com/blog/supplements-lifestyle-factors-influence-tnf-interleukin-6-il-6/ - this should be read with your context, though, not from his or a relatively healthy person's

http://m.jlr.org/content/48/4/751.full